Breast cancer is the leading cancer in women across all states in urban India. The crude rate and age-adjusted risk vary from 12.7–34.8 to 13.9–41 per 100,000 populations across the several states involved in the ICMR-sponsored population-based cancer registry program.[1] Most of the 25 population-based cancer registries enrolled in this program reported a rising trend for breast cancer, especially in Bangalore, Delhi, Barshi, Bhopal, Chennai with an annual percentage change from 2% to 2.8%. Survival is a key index of the overall effectiveness of health services in the management of patients with cancer and survival patterns can be used to drive national cancer strategies, as have been used across several nations in the world.[2] Ethnic differences in breast cancer survival have been documented and their influence on survival rates in different parts of the world.[3] Same prognostic factors may not apply to a given race, for example, breast cancer survival for estrogen receptor and progesterone receptor (ER/PgR)-positive tumors in black patients was lower than similar tumors in Caucasian patients.[4] This retrospective audit was undertaken to evaluate 5-year survival and the prognostic factors in breast cancer patients registered in the year 2009 at a tertiary cancer center in India.

» Materials and Methods

A total of 3042 new breast cancer patients registered in 2009 at Tata Memorial Centre (TMC), Mumbai. After excluding patients lost after initial examination and benign tumors, 2192 patients with breast cancer were selected for further analysis. The usual workup for these patients included a complete blood hematocrit, biochemistry, bilateral mammography along with breast ultrasonography in selected cases. In locally advanced breast cancers (LABCs), a metastatic workup included a chest X-ray, ultrasonography of the abdomen and pelvis or computed tomography scan of the thorax/abdomen/pelvis in selected cases and bone scan.

In 2009, women with early breast cancer (EBC) were offered breast-conserving surgery (BCS) in the absence of known contraindications, i.e., inability to take radiation therapy, extensive microcalcifications or multicentric disease, persistent positive margins, and inflammatory breast cancer. If the patient presented with locally advanced cancer or large operable breast cancer or the breast tumor ratio was inadequate for conservation, neoadjuvant chemotherapy (NACT) was offered to downsize the tumor and reviewed for feasibility of postchemotherapy breast conservation surgery. Some cases were considered for conserving surgery with a pedicled latissimus dorsi flap for partial volume replacement. Those who were not eligible for conservation or did not chose it were offered a modified radical mastectomy (MRM). About 1%–2% of the women who underwent an MRM also had whole breast reconstruction. All patients who were operated for breast cancer underwent level III axillary clearance. Ongoing studies were being conducted to evaluate the role of sentinel lymph node biopsy and low axillary sampling in the clinically node-negative population.

Standard reporting formats were used for histopathological reporting. For reporting of biomarkers, a >1% tumor nuclei showing any intensity of staining was considered as positive for ER and PgR. For the human epidermal growth factor receptor 2 (Her2neu) interpretation, the cutoff >30% cells showing complete membrane staining was interpreted as positive.

Our standard approach for neoadjuvant therapy has been to use the sandwich approach. The neoadjuvant regimen comprised of anthracycline-based therapy (AC [doxorubicin and cyclophosphamide]/EC [epirubicin and cyclophosphamide]/FAC/FEC [5-fluorouracil, doxorubicin or epirubicin, and cyclophosphamide]) for 4 cycles followed by surgery. Patients with LABC, post-NACT followed by surgery, received one of the taxane regimens in the adjuvant setting (3 weekly paclitaxel × 4/ weekly paclitaxel × 12/ docetaxel based). Among patients who underwent upfront surgery, those with lymph node-positive disease received an anthracycline-taxane-based regimen, while those with lymph node-negative disease received 6 cycles of anthracyclines. Patients with Her2neu-positive breast cancer were offered neoadjuvant and adjuvant trastuzumab. Premenopausal women with hormone receptor (HR)-positive disease received 5 years of adjuvant tamoxifen, while postmenopausal women were given 5 years of an aromatase inhibitor. Only 21% of Her2neu-positive women could afford Her2neu in this study, and hence, data for trastuzumab vs no trastuzumab are not studied.

All women undergoing breast conservation surgery were advised 5 weeks of adjuvant radiation to the involved breast. Women with early breast cancer received 45 Gy in 25 fractions while women with LABC received 50 Gy in 25 fractions to the whole breast. This was followed by boost to the tumor bed to a dose of 15 Gy in 6 fractions with en face electrons. All women underwent a two-dimensional radiotherapy planning for breast as well as the tumor bed. Postmastectomy women with T1-2N0-1 stage were not offered adjuvant radiation. Women presenting with LABC were given adjuvant radiation to the chest wall to a dose of 45 Gy in 20 fractions over 4 weeks.

All women with four or more positive axillary lymph nodes and those receiving NACT for LABC (irrespective of number of positive nodes) received adjuvant radiation to the chest wall or breast and supraclavicular fossa. The dose was 50 Gy in 25 fractions in case of breast conservation and 45 Gy in 20 fractions in case of postmastectomy. Patient follow-up was updated through electronic medical record and by retrieving patient files from the medical record department. The survival analysis was done using the (IBM) SPSS 20 PASW software. Disease-free survival (DFS) or outcome was analyzed in women with EBC and LABC, who received definitive treatment at our institute and with at least a 3-month follow-up.

» Results

Our cohort of 2192 patients included 2171 women and 21 male patients with breast cancer. The median age at presentation was 50 years (range 18–94). Of these, 888 (40.5%) were EBCs, 833 (38%) were large operable or LABCs, and the remaining 471 (21.5%) were metastatic (both de novo and recurrent). The analysis has been carried out separately by stage at presentation for only the early and locally advanced cancers. [Table 1] shows the demographic features of the patients with EBC and LABC who received treatment at our center in 2009.

In 2009, there were 888 patients who were registered at our institute with T1or T2 and N0-1 EBC. The median age at presentation was 50 years (range 20–84). Of these, 709 underwent definitive surgery at our institute. The remaining 179 had undergone definitive surgery elsewhere and consulted at TMC for further adjuvant therapy planning or had irregular follow-up. Of these 709 (7 men and 702 women, 44.3% pre- and peri-menopausal, and 54.7% postmenopausal), 80 received chemotherapy before surgery, either for facilitating BCS or due to the presence of postexcision biopsy induration. Upfront surgery was offered in 622 of these 702 women. Of these, 63.2% underwent BCS while rest had MRM. Use of chemotherapy allowed BCS in 75% (60 of 80) women who were previously deemed unsuitable for the same.

The histopathology was an infiltrating duct carcinoma (not otherwise specified) in 96.3% cases, Grade III in 79.1%, extensive intraductal component in 15.1%, and lymphovascular emboli (LVE) positivity in 14.1%. The median pathological tumor size in women who did not receive chemotherapy before definitive surgery was 2.5 cm (range 0.1–5.0) and node positive rate was 41.3%. The tumors were hormone sensitive and expressed ER and/or PgR in 58.7% cases; Her2neu overexpression on IHC (3+) was seen in 17%, while 4.9% were Her2neu equivocal and 28.5% were triple negative breast cancer (TNBC).

Large operable and locally advanced breast cancer

Of the 833 patients who were deemed to have larger tumors (T3, N0-1) and locally advanced nonmetastatic (T4 any N, any T N2/N3), the median age at presentation was 48 years (range 18–86). Information was incomplete in 145 out of the 833 cases (17.4%) and hence were not included in the analysis. Of the remaining 688 patients (1 male, 687 women of whom 49.3% were pre- and peri-menopausal, and 50.7% postmenopausal), 150 (22%) did not receive neoadjuvant systemic therapy and were mostly T3N0-1 disease who underwent upfront surgery as in MRM. A total of 537 women received NACT, mostly as anthracycline-based chemotherapy. All were assessed after chemotherapy for feasibility of BCS. The median tumor size at presentation was 6 cm (2–25 cm). BCS was feasible in 43.2% after chemotherapy, with postchemotherapy node positivity rate of 58.6%. Most tumors were infiltrating duct carcinomas, i.e., 97.8%. All women completed remaining chemotherapy after surgery as per guidelines followed by radiation therapy and hormone therapy where indicated. Hormone receptors were expressed in 51% tumors in LABC, while Her2neu was positive (score 3+) in 15.6%, and 36% were TNBC.

Survival analysis

The final survival analysis included 1354 patients (670 EBC and 684 LABC). The median follow-up in EBC was 75.5 months and for those with LABCs was 71.2 months.

Current practices are governed by standard guidelines and define outcomes. TMH has been actively involved in drafting guidelines in cancer management https://tmc.gov.in/NCG/docs/PDF/Breast/Breast_Cancer.pdf and has been following them for almost 2 decades. In addition, treatment protocols are also being tested in randomized setting and have evolved over the past few years with observed benefit on outcomes. The 2009 data give us a snapshot of trends over the last 8 years and outcomes of patients managed as per guidelines and evidence-based medicine. It also provides us with a benchmark to refer to with aim to move higher than these set goals in improving outcome of cancer in days to come.

Varied clinicopathologic features of breast cancer have been reported across India reflecting the urban-rural divide and varying socioeconomic status.[5],[6],[7],[8],[9] Most studies from India report a median age of women with breast cancer as 47–50 years which is a decade younger than Western population. Although in a previous study from our institute 68% women were <50 years,[10] in the present audit, nearly equal numbers of women were above and below 50 years of age. The distribution of cases by stages also appears to vary slightly. The early cases accounted for 40%, and an equal number of LABC cases were seen in 2009. In addition, 21.5% were de novo metastatic or recurrent cancers. Although many reports from India report higher incidence of advanced cancer, in the present study after excluding metastatic and recurrent cases, 709 (51%) were EBC and 688 (49%) were LABC.

Very low rates for BCS have been reported in India from most centers, and reasons are mainly due to unacceptability of safety of conservative surgery by physicians and thereafter the patients.[9],[11] In this audit, 63.2% of the EBC patients underwent BCS, which is lower than those reported in some Western cohorts and may be due to several reasons such as patient's inability to stay in hospital for radiotherapy and compliance issues. A report from Mayo Clinic Rochester documented that mastectomy rates have increased in recent years due to prevalent use of MRI breast for preoperative workup;[12] we however do not use MRI for pre-BCS evaluation, except for highly selected cases.

Special types of invasive carcinomas were rare in our patient population in the present study. A SEER analysis of Asian Indian and Pakistani women with breast cancer reported a slightly higher frequency of invasive ductal carcinoma (69.1 vs. 65.6%) and lower invasive lobular carcinoma (4.2% vs. 8.2%) compared to Caucasian women.[13] One of the reasons could be due to lower use of postmenopausal hormone replacement therapy in Asian versus Western women.[14] An older study of patterns of breast cancer in 10 hospitals in the city of Mumbai revealed interesting tumor differentiation patterns based on socioeconomic status. Large referral institutes like ours had 80% of Grade III cancers, while in private hospitals of Mumbai, Grade II cancers were equal in number to Grade III cancers. Grade I tumors formed 9.5% to 20% with private hospitals recording higher incidence of Grade I tumors.[15] As far as Grade II tumors are concerned, they constituted 18.7% of EBC and 11.1% of LABC patients in this study.

There have been very few reports on survival from cancer in India, mainly because of poor patient follow-up and inadequate system of registration of death. A previous retrospective study from our institute published in 2008, reported 20-year follow-up data on OS and DFS in early-stage breast cancers that underwent BCS. The study reported the 5- and 10-year overall survival (OS) of 87% and 77% and DFS rate of 76% and 68%, respectively.[16] Subsequently, in 2010, we published the results of a prospective randomized clinical trial in EBC, which completed accrual in 2004. The 5-year DFS in the control arm of that study was reported as 70.2% and an OS of 78.4%.[17] The 5-year DFS in EBC in 2009, reported in this current cohort is 85.5%, shows an improving trend. This may be an apparent slight inflated figure due to two reasons, first being a retrospective study cohort, and second, there may have been a selection bias in the follow-up data.

Another retrospective audit from India reported in 2016 on 1213 women over a 6-year period (2004–2010) managed at a tertiary breast unit comparing outcomes in TNBC (n = 249) versus other tumors. They reported TNBC occurring at younger age, being higher grade and worse DFS and OS inspite of better chemoresponsiveness. They reported DFS of 89.2% and OS of 81.8% in all stages put together for women with TNBC. The non-TNBC fared better mainly in Stage III while the difference was not so obvious in lower stages.[18]

An older study of 2080 cases of invasive female breast cancer registered in the Madras cancer registry during 1982–1989 reported an OS rates of 48% at 5 years and relative survival of 51%.[19] A Bangalore population-based registry reported 1514 breast cancer patients with 5-year survival as 42.3% and the corresponding relative survival as 46.8%.[20]

Traditional prognostic factors influencing survival in invasive breast cancer include age,[21] node status,[22] tumor size,[22] tumor grade,[23],[24] and LVE.[25] A large review of all survival studies documented that tumor size, nodal status, and tumor grade remained the most important prognostic factors for long-term survival although their role decreased over time.[26] In a study assessing prognostic factors in BCS at our institute, we reported LVE or invasion as the strongest independent adverse factor for all failure and survival.[16]

Age did not impact survival rate in the present study, but node status and hormone receptor status proved to be important prognostic factors in both EBC and LABC. One study of 189 patients from Kerala also reported node status and hormone receptors as significant for survival.[27]

In 2006, a retrospective audit of 664 cases of LABC with 32-month follow-up with survival data was published from TMC. Following response to chemotherapy, 28% women with LABC underwent breast conservation surgery. The 5-year DFS was reported as 37% for whole group, 72% for women who underwent BCS as against 38% after mastectomy.[28],[29] It appears that the rate of breast conservation has increased in women with LABC following chemotherapy. In the present cohort, 43.2% underwent BCS. Postchemotherapy response is one of the most important factors that emerged significant in LABC as defined by the residual lymph nodes positive for metastases.[30],[31] A large review of international trials included 11,955 patients and documented that complete response in nodes and at primary site irrespective of DCIS was the most important predictor of survival.[32] In our previous study, predictors of response to chemotherapy included in addition to lymph nodes, smaller T size, hormone receptor negative tumors, the absence of LVE, younger age, and absence of skin involvement.[33] In our present study in the Cox regression model, mastectomy patients fared worse then BCS as mastectomy was done in poor responders while BCS is offered to responders.

There is a lot of heterogeneity in rates for hormone receptor positivity in the country with rates from 38% to 70%, and for Her2neu, the range is from 16.7% to 36.7%. The current cohort demonstrated a change in biomarker groups between EBC and LABC, with relatively more ER- and/or PgR-positive tumors in EBC (49.6% vs. 41.1%) and more TNBC (28.5% vs. 36.1%) in LABC. While the percentage of Her2neu-positive tumors did not change across the stages of breast cancer (17% vs. 15.6%). Hormone receptor negative status was a poor prognostic factor in both EBC and LABC in the study cohort. A recent review of long-term recurrence rates in patients enrolled in BIG trial documented that during the first 5 years, patients with estrogen receptor-positive disease had a lower annual hazard when compared with those with ER-negative disease; however, beyond 5 years, patients with ER-positive disease had higher hazards.[34]

In 2011, we reported the usage of Her2 targeted therapy at TMC among women treated in 2008.[35] Only 4% of women in 2008 could afford to receive anti-HER2 treatment in 2009 while another 4% were offered through assisted programs. It is well-known that Her2neu-positive patients who do not receive trastuzumab fare worse than TNBCs[36] and this was evident in our study cohort too.

» Conclusions

The importance of auditing institutional data cannot be stressed more strongly to help understand better the benefits of current practices based on evidence. It also serves as a benchmark for comparing outcomes following further improvements in practices that can be brought into patient care with advancing technology and medical treatment.